Amyloid-? (A?) plaques and tau neurofibrillary tangles, as well as neuronal death, are the pathologic hallmarks of Alzheimer's disease (AD). Therapeutic efforts focused on A? have thus far failed, underscoring the urgent need for alternate approaches, particularly those that can target early AD. Aberrant tau in the locus coeruleus (LC), the major noradrenergic nucleus in the brain that regulates attention, arousal, stress responses, and cognition, is the earliest detectable AD-like neuropathology in the human brain, and LC degeneration is ubiquitious in later AD. Recent research indicates that early LC dysfunction may contribute to prodromal AD symptoms such as depression, anxiety, and sleep disorders, while later LC degeneration exacerbates cognitive impairment. Although these data suggest that the LC is a promising therapeutic target in AD, almost nothing known about how pathogenic tau impacts LC function and survival. We have developed a viral vector that drives the expression of wild-type human tau exclusively in LC neurons, which over time becomes hyperphosphorylated and misfolded, thus recapitulating the earliest forms of human AD. We will use this novel tool to study the consequences tau pathology in the LC. In Aim 1, we will determine the impact of different forms of aberrant tau on LC neuron morphology, survival, and local inflammation, and assess the potential of LC-derived tau pathology to spread to interconnected forebrain regions. In Aim 2, we will use in vivo electrophysiology and behavioral paradigms to evaluate how tau pathology affects LC activity and performance in neuropsychiatric and cognitive domains. In Aim 3, we will combine optogenetics and fMRI to determine how aberrant tau influences LC-forebrain functional connectivity. Completion of these aims will lay the groundwork for LC/tau-based therapies for early AD.